FI121588B - Process for the preparation of opioid formulation - Google Patents

Abstract

Oral sustained release opioid formulation comprises: an opioid analgesic, a retardant material to cause the opioid analgesic to be released at a rate to provide an analgesic effect after oral admin. to a human patient for 24 hrs, the formulation when administered in humans providing an initially rapid rate of rise in the plasma conc. of the opioid characterised by providing an absorption half-life of 1-8 hrs. in the fastened state. Method for titrating human patients with a sustained release oral opioid formulation comprises: 1) administering to a human patient on a once-a-day basis a unit dose of an oral sustained release formulation comprising a dose of an opioid analgesic and a retardant material as described above, 2) monitoring pharmacokinetic and pharmacodynamic parameters elicited by the formulation in the human patient and determining whether the pharmacokinetic and/or pharmacodynamic parameters are appropriate to treat the patient on a repeated basis, 3) titrating t he patient by adjusting the dose of the opioid analgesic administered to the patient by administering a unit dose of the sustained release opioid analgesic formulation if it is determined that the pharmacokinetic and/or the pharmacodynamic parameters are not satisfactory or maintaining the dose of the opioid analgesic in the unit dose at a previously administered amt. if the pharmacokinetic and/or pharmacodynamic parameters are deemed appropriate, 4) continuing the step 3 titration by adjusting the dose of the opioid analgesic until appropriate steady state pharmacokinetic and/or pharmacodynamic parameters are achieved in the patient, and 5) continuing the admin. of the dose of the opioid analgesic in the oral sustained release formulation on a once-a-day basis until treatment is terminated.

Description

Process for the preparation of an opioid formulation Förfarande för framställning av opioidformulation

BACKGROUND OF THE INVENTION

The present invention relates to bioavailable slow release pharmaceutical formulations of analgesic drugs, particularly opioid analgesics, which provide a long duration of action when administered orally.

All sustained release formulations are intended to provide a longer duration of pharmacological action after administration of the drug than is conventionally obtained with immediate release dosage forms. Such longer response times have many therapeutic benefits that are not achieved with similar short-acting immediate release formulations. This is especially true for cancer patients or other patients whose moderate or severe pain needs to be alleviated when the blood levels of the analgesic opioid drug need to be maintained at a therapeutically effective level to relieve pain. If conventional fast-acting drugs are not carefully dosed, at short intervals, to maintain steady-state drug levels in the blood, active drug levels have peaks and valleys due to rapid absorption, systemic excretion and metabolic inactivation, which causes particular problems in maintaining the analgesic effect.

25

Prior art teachings on the preparation and use of such compositions providing slow release of the active compound from a carrier inhibitory agent mainly concern the release of the active agent into the physiological fluid of the metabolic region. However, it is generally known that the mere presence of an active agent in gastrointestinal fluids does not in itself confer bioavailability.

2

Due to absorption, the active drug must be in solution. The soaking time required to dissolve a certain proportion of the active ingredient in a dosage unit form is determined as the proportion of the amount of active drug released from the dosage unit form over a period of time based on a test method performed under standard conditions. Gastric physiological fluids are media for determining the dissolution time. Current state of the art provides many satisfactory test methods for measuring the dissolution times of a pharmaceutical composition, and these test methods are described in public worldwide handouts.

10

The primary principle in the use of opioid analgesics when treating chronic pain is to individualize the dosages to meet different and varied opioid requirements among different patients and in a single patient. The importance of titration is emphasized by analgesics. 15 Titration to the appropriate dose for a particular patient is necessary because of the many differences between individuals in their response to different doses of opioids. Although many factors contribute to large inter-individual and intra-individual differences in response to opioid analgesics, one important factor is related to large individual differences in metabolism and pharmacokinetics.

The opioids most efficiently titrated are those with relatively short elimination half-lives in the range of 3 to 5 hours (e.g., morphine, hydromorphone, oxycodone) compared to analgesics with long (12 to 72 to 25 hours) and more variable half-lives (e.g. Methadone, levorphanol). Drugs with shorter half-lives approach steady state concentrations in about a day rather than several days or weeks or more. Only in the steady state can one expect that the balance between efficacy and side effect will follow a particular dosing schedule. By relying on the patient to be in a steady state for 30 days, e.g., about a day after a dose, it can be more quickly evaluated if the dose is appropriate for this individual.

3

Once-daily oral dosage forms have been developed in the art and are commercially available. However, there are currently no commercially available 24-hour analgesic 5-opioid formulations; however, experience with 12 hour sustained release formulations has led to a general understanding within the medical community that it is essential to titrate a patient to receive analgesic opioid therapy using an immediate release analgesic opioid dosage form, such as a parenteral or an immediate release formulation. Only when suitable constants have been achieved in a patient using immediate release opioid formulations can the patient be switched to a slow release oral opioid formulation.

Consequently, it would be desirable for users to have a sustained-release analgesic opioid formulation that provides appropriate pharmacokinetic parameters (e.g., absorption profile) and an appropriate pharmacodynamic response in the patient (e.g., pain relief) so that the same dosage form can be used for patient titration. , receiving analgesic opioid therapy, and chronic maintenance therapy following patient titration. This would eliminate the need to first treat the patient with the immediate release opioid dosage form before switching the patient to a slow release dosage form for chronic treatment as discussed above. Preferably, slow release formulations provide an effect that lasts for more than about 12 hours so that the drug can be administered to a patient only once a day. Preferably, the sustained release dosage form not only provides effective analgesia for more than about 12 hours, but also provides a pharmacokinetic and pharmacodynamic profile that allows the patient to receive analgesic opioid therapy, titration, and chronic therapy with the same slow release dosage form.

4

Many of the currently available analgesic oral opioid formulations need to be administered every four to six hours; some are formulated for less frequent 12 hour dosing.

There is also a need to develop a drug formulation that provides an absorption profile suitable for titrating a patient, receiving analgesic opioid therapy, and also providing a slow release of the opioid analgesic sufficient to administer the analgesic agent for only about 12 hours. This would eliminate the need to first titrate the patient with immediate release 10 opioid analgesic dosage forms (e.g., gastrointestinal, oral, rectal) and then convert the opioid analgesic to a slow release form.

Morphine, considered to be a prototype of opioid analgesic, has been formulated in controlled release formulations (i.e., MS Contin tablets, commercially available from Purdue Frederick Company; and Kapanol®, commercially available from FH Faulding and Company; and Oramorph® SR, previously is referred to as Roxanol® SR, commercially available from Roxane).

20

An oral opioid formulation that would provide a long-lasting analgesic effect without major side effects would be highly desirable. This provides a sustained release oral formulation of an opioid analgesic that is bioavailable and provides effective steady-state conditions (e.g., plasma values) for 25 drugs when administered orally with an analgesic duration of effect of about 24 hours or more.

OBJECTS AND SUMMARY OF THE INVENTION

It is therefore an object of the present invention to provide a method of treating patients with moderate to severe pain in a pharmaceutical dosage form of opioid analgesic, suitable for once daily administration.

It is yet another object of this invention to provide a method of treating patients with a once daily analgesic opioid formulation that provides a better analgesic effect than the preferred Q12H (every 12 hours) analgesic therapies.

Another object of the present invention is to provide an analgesic dosage form of opioid which provides slow release of the opioid and which can also be used to titrate a patient receiving analgesic opioid therapy.

In accordance with the foregoing and other objects, the present invention relates in part to the surprising discovery that to obtain a 24 hour 15 dosage form of an opioid analgesic, it is critical to formulate a slow release formulation with an analgesic to initially provide rapid opioid release at low effective analgesic concentration. that have measurable, albeit not significant pain at the time of dosing. Due to the unique 20 release profile of the dosage form of the invention, it is possible to use the single dose form of this invention to titrate a patient undergoing analgesic opioid therapy while providing slow daily opioid in order to release the analgesic at a rate of action which provides an analgesic effect after oral administration in a human subject for at least about 24 inches.

The inventive formulations, when administered to humans, initially induce a rapid increase in the plasma concentration of the opioid, which is known for providing an absorption half-life of 1.5 to about 8 hours. In preferred 6 embodiments, the inventive once-daily oral slow-release formulations provide an absorption half-life of 2 to about 4 hours.

This invention also relates to a method for titrating human patients with a slow release oral opioid formulation. The first step of this method comprises administering to a human patient once daily a dosage unit of an oral opioid formulation according to the invention, which formulation is described above and in the following paragraphs. Thereafter, the method further comprises adjusting the pharmacokinetic and pharmacodynamic parameters of said formulation in said human patient and determining whether said pharmacokinetic and / or pharmacodynamic parameters are suitable for repeated treatment of said patient. The patient is titrated by regulating the mercy of said opioid analgesic, which is administered to the patient. This is accomplished by administering either a unit dose of said 15 slow release opioid analgesic formulation containing a different amount of an opioid analgesic, if it is determined that said pharmacokinetic and / or story dynamic parameters are unsatisfactory, or alternatively, maintaining or pharmacodynamic parameters appear to be appropriate. Further titration is continued by further adjusting the dose of the opioid analgesic until appropriate steady-state pharmacokinetic / pharmaco-dynamic parameters are achieved in the patient. Thereafter, the dosage of the opioid analgesic in the oral slow-release formulation is continued once daily until treatment is stopped.

25

The term "bioavailability" is defined for purposes of the invention as the bioavailability of a drug (e.g., an opioid analgesic) in dosage unit forms.

For purposes of the present invention, the term "slow release" is defined as the release of a drug (eg, an opioid analgesic) at a rate such that blood (eg, plasma) values are maintained within the therapeutic range but below toxic values for about 24 hours or longer.

The phrase "rapid increase" in plasma concentration of an opioid, for purposes of the present invention, is defined as providing formulation with a Ty 2 (abs) or absorption half-life of about 1.5 hours to about 8 hours.

The term Ty 2 (abs) is defined, for purposes of the present invention, to be the time required for half of the absorbed dose of the opioid to pass into plasma. This value is calculated as a "true" value (which takes into account the effect of the elimination process) rather than a "visible" absorption half-life.

The term "constant" means that the plasma level of a given drug has been reached. This level, which is thereafter maintained by the drug, is the minimum therapeutically effective level of this drug or higher, but less than the minimum toxic effect of this drug. The therapeutic value for opioid analgesics is determined in part by the amount of pain relief achieved in a particular patient. It is well understood by medical practitioners that the measurement of pain is very subjective and that a great deal of individual variation can occur between patients.

The terms "maintenance therapy" and "chronic therapy" are defined, for purposes of the present invention, as a drug treatment to be administered to a patient when the patient is titrated with an opioid analgesic to a steady state as defined above.

BRIEF DESCRIPTION OF THE DRAWINGS

30 8

The following drawings illustrate embodiments of the present invention and are not intended to limit the scope of the invention claimed.

Figure 1 is a graph of mean quiescent versus time curve for 5 examples 1 (in fasted state);

Figure 2 is a graph of mean quiescent versus time curve of Example 2 (in fasted state); Figure 3 is a graph showing the average respiration rate versus time curve of Example 1 (in fasted state);

Figure 4 is a graph of average respiration rate versus time curve of Example 2 (in fasted state); 15

Figure 5 is a graph showing the average pupil size versus time curve of Example 1 (in fasted state);

Figure 6 is a graph of average pupil size versus time curve for Example 2 (in fasted state);

Fig. 7 is a graph of average subject questionnaires versus time curve of Example 1 (in fasted state); Figure 8 is a graph of average subject questionnaires versus time curve of Example 2 (in fasted state);

Fig. 9 is a graph of the mean plasma morphine concentration time profile obtained from Comparative Example (MS Contin 30 mg) 30 (fasted state) versus the capsules of Example 1 (fed and fasted) and the capsules of Example 2 (fasted); 9

Figure 10 is a graph of the mean plasma morphine concentration time profile obtained from Comparative Example (MS Contin 30 mg) (in fasted state) and compared to the capsules of Example 3 (fed and 5 fasted state);

Fig. 11 is a graph of mean quiescent versus time curve of Example 3 (in fasted state); Figure 12 is a graph of average respiration rate versus time curve of Example 3 (in fasted state);

Figure 13 is a graph of average pupil size versus time curve of Example 3 (in fasted state); 15

Figure 14 is a graph of the average modified specific drug effect versus time curve of Example 2 (in fasted state).

DETAILED DESCRIPTION

20

Even at steady state doses of opioid analgesics, many patients will have measurable or significant pain. The state of the art approach to controlled release opioid therapy is to provide formulations with zero order pharmacokinetics and minimal peak opioid levels in fluctuations at 25 repeated doses. This zero-order release also gives a very slow absorption of the opioid and a generally steady-state serum concentration curve over time. A steady-state serum concentration curve is generally preferred because it has little effect on the steady state condition when efficacy is required, but the side effects common to opioid analgesics are minimized. However, when formulating slow release opioids in this manner, it has been found that patients will feel significantly uncomfortable the next time the opioid is administered orally.

It has now surprisingly been found that faster and greater analgesic efficacy is achieved with 24-hour oral opioid formulations which do not have a substantially smooth serum concentration curve but which, on the other hand, have a faster initial opioid release so that an effective minimum analgesic concentration can be obtained measurable though not significant pain at dosing. Even with standard doses of oral opioid analgesics, it has been found that most patients will have measurable or significant pain and would greatly benefit from the new oral opioid treatment presented herein. Also surprising and unexpected is the fact that although the methods of the present invention achieve a faster and greater analgesic effect, there are no significantly greater side effects that would normally be expected from higher peak plasma concentrations.

Determining effective analgesic plasma opioid levels (e.g., morphine) is very complex. However, there is generally a "minimum effective analgesic concentration" (MEAC) for a particular opioid in plasma below which analgesia is not achieved. Although there is an indirect relationship between plasma amorphine levels and analgesia, for example, higher plasma levels are generally associated with better analgesia. There is a germination time or hysteresis between peak plasma opioid levels and peak drug effects. This applies to the treatment of pain with opioid analgesics in general.

The inventive slow-release once-a-day formulations are characterized by the fact that they are designed to induce a rapid increase in the plasma concentration of said opioid, characterized in that it provides an absorption half-life of about 1 to about 8 hours when slowly administered orally. the released formulation is dosed in fasted state 11 (i.e., without food). In certain embodiments, the absorption half-life is preferably from about 1 to about 6 hours, more preferably from about 1 to about 3 hours.

The formulations of the invention are further characterized by having a surprisingly fast peak plasma concentration of the drug (i.e., tmax). The sustained release formulations of this invention may have a t max of from about 2 to about 10 hours. In certain preferred embodiments, the timix of these formulations may be from about 4 to about 9 hours.

The administration of the 24 hour oral slow release opioid formulations of this invention will release certain pharmacodynamic targets more strongly in the early part of the plasma concentration curve (e.g., 4-8 hours after oral administration) such as sedation, respiratory rate, pupil size, and / or combined lengths of time. given after each treatment in the series (i.e., oral dosage form administration). Other analgesic efficacy measurements, such as the sum of pain intensity difference (SPID) and total pain relief (TOTPAR), have higher numerical scores with these methods, which in many cases also result in fewer side effects (which are generally mild to moderate drowsiness, nausea and / or dizziness) ).

The analgesic opioid compounds which may be used in the present invention include alfentanil, allylprodine, alphaprodine, anileridine, benzylmorphine, bezitramide, buprenorphine, butorphanol, clonitazene, codeine, cyclazocine, desomorphine, dextromoramide, dxtromoramide, dxtromoramide, , dioxaphetyl butyrate, dipipanone, eptazocine, ethoheptazine, ethylmethylthiambutene, ethylmorphine, etonitazene fentanyl, heroin, hydroeodone, hydromorphone, hydroxypethidine, 30 isomethadone, ketobemidone, levallorphan, levorphanol, levorphan 12 myrophine, nalbuphine, narcein, nicomorphine, norlevorphanol, normethadone, nalorphine, normorphine, norpipanone, opium, oxycodone, oxymorphone, papaveretum, pentazocine, phenadoxone, phenomorphan, phenazocine, phenoperidine, phenoperidine ram, propoxyphene, sufentanil, tramadol, tilidine, their salts and any mixtures thereof, mixtures of mu-agonists and antagonists, mu-antagonist combinations and the like. The opioid analgesic may be in the form of the free base, salt, complex, etc. In certain preferred embodiments, the opioid analgesic is selected from the group consisting of hydromorphone, oxycodone, dihydrocodeine, codeine, dihydromorphine, morphine, buprenorphine, salts of some of the foregoing.

A preferred embodiment of the oral sustained release opioid dosage form of this invention contains hydro-morphone as the therapeutically active ingredient in an amount of about 4 to about 64 mg of hydro-morphone hydrochloride. In another preferred embodiment, the analgesic opioid comprises morphine, and the slow-release oral dosage forms of this invention contain from about 5 mg to about 800 mg of morphine. Alternatively, the dosage form may contain equivalent amounts of other hydromorphone or morphone 20 salts or base. In certain preferred embodiments where the opioid is morphine, the maximum plasma concentration is from about 2 ng / ml to about 14 ng / ml, and preferably from about 3 ng / ml to about 8 ng / ml, based on a 30 mg dose of morphine sulfate. In another preferred embodiment, the analgesic opioid comprises oxycodone. The sustained release oral dosage forms of this invention contain from about 5 mg to about 400 mg oxycodone. In some other preferred embodiments, the dosage form contains a suitable amount of another opioid analgesic to obtain a substantially equivalent therapeutic effect.

The slow release dosage forms of the present invention generally achieve and maintain therapeutic levels that are not substantially more potent and / or do not result in substantially more severe side effects, such as nausea, vomiting, or somnolence, often associated with high blood levels of opioid analgesics. It is also worth suggesting that the use of these dosage forms results in a lower risk of drug addition. In addition, the slow release dosage forms of the present invention preferably release the opioid analgesic at a rate independent of pH, e.g., in the range of 1.6 to 7.2. In other words, the dosage forms of the present invention avoid "abrupt dose erasure" when administered orally.

In this invention, oral opioid analgesics are formulated to provide a longer duration of action of the analgesic activity, which can only be administered once daily Surprisingly, these formulations, in the case of formulations corresponding to daily doses of conventional immediate release drugs, have a lower risk of serious adverse drug reactions. administered at a lower daily dose than conventional oral medications, but pain can be kept under control.

The retarding material used in the sustained release formulations of the invention may be those known in the art, including, but not limited to, acrylic polymers, alkylcelluloses, shellac, zein, hydrogenated vegetable oil, hydrogenated castor oil, and mixtures of some of the foregoing.

In certain preferred embodiments of the present invention, sustained release opioid dosage forms comprise a plurality of substrates comprising the active ingredient coated with a sustained release coating comprising a retarding agent. The coating formulations of this invention should be able to produce a strong, continuous film that is smooth and excellent, capable of supporting pigments and other coating additives, is non-toxic, inert, and contact dry.

The sustained release formulations of this invention may be used with any multiparticulate system such as beads, spheroids, microspheres, grains, pellets, ion exchange resin beads, and other multiparticulate systems to provide the desired slow release of the therapeutically active agent. Beads, granules, spheroids or pellets, etc., prepared in accordance with the present invention may be presented in capsule or any other suitable unit dosage form.

When the substrates of the present invention are inert pharmaceutical beads, the inert pharmaceutical beads may be from about 8 mesh to about 50 mesh. In certain preferred embodiments, the beads are e.g. nu pariel 18/20 beads.

In certain preferred embodiments of the present invention, slow release opioid dosage forms comprise a plurality of substrates comprising an active ingredient coated with a sustained release coating. The coating formulations of this invention should be able to produce a strong, continuous film that is smooth and excellent, capable of supporting pigments and other additives, is c-toxin, inert, and contact dry.

In order to obtain a slow release of the opioid sufficient to produce an analgesic effect for a prolonged period as disclosed herein, a substrate comprising a therapeutically active agent may be coated with a sufficient amount of a hydrophobic agent, although the coating may have a weight gain of about 2% to about 30%. higher depending on the physical properties of the 25 opioid analgesics used, and the desired release rate, among others.

To obtain an opioid slow release sufficient for the same analgesic effect for a longer period of time as disclosed herein, a substrate comprising a therapeutically active agent may be coated with a sufficient amount of a retarding material to provide a weight gain of about 2 to about 30%. be greater depending on the physical properties of the opioid analgesic compound used, and the desired rate of release, inter alia.

The solvent used for the retardant material, which is typically hydrophobic, may be any pharmaceutically acceptable solvent, for example water, methanol, ethanol, methylene chloride and mixtures thereof. However, it is preferred that the coatings be based on hydrogen dispersions of hydrophobic materials.

In certain preferred embodiments of the present invention, the hydrophobic polymer comprising the sustained release coating is a pharmaceutically acceptable acrylic polymer, for example, but not necessarily, copolymers of acrylic acid and methacrylic acid, methyl methacrylate, ), methacrylic acid-alkyl amide copolymer, poly (methyl methacrylate), poly (methacrylic acid anhydride), methyl methacrylate, polymethacrylate, poly (methyl methacrylate) copolymer, polyacrylamide, aminoalkyl methacrylate glycolate.

20

In certain preferred embodiments, the acrylic polymer consists of one or more ammonium methacrylate copolymers.

Ammoniomethacrylate copolymers are well known in the art and are described in standard NF XVII as fully polymerized copolymers of acrylic and methacrylic acid esters with a small proportion of quaternary ammonium groups.

In a preferred embodiment, the acrylic coating is an acrylic resin lacquer used in the form of an aqueous dispersion such as that commercially available from Rohm Pharma under the trademark Eudragit®. In other preferred embodiments, the acrylic coating comprises a mixture of two acrylic resin varnishes 16 commercially available from Rohm Pharma under the trademarks Eudragit® RL 30 D and Eudragit® RS 30 D. Eudragit® RL 30 D and Eudragit® RS 30 D are acrylic and methacrylic esters, a small amount of quaternary ammonium groups, wherein the molar ratio between the ammonium groups and the remaining neutral methacrylic acid esters is 1:20 in Eudragit® RL 30 D and 1:40 in Eudragit® RS 30 D. The average molecular weight is about 150,000. The code designations RL (High Permeability) and RS (Low Permeability) relate to the permeability properties of these substances. Eudragit® RL / RS mixtures are insoluble in water and in digestive fluids. The coatings formed therefrom, however, are swellable and permeable in aqueous solutions and digestive fluids.

The Eudragit® RL / RS dispersions of the present invention may be mixed together in any desired ratio to provide a sustained release formulation having the desired dissolution profile. The desired sustained release formulations may be obtained, for example, from retardation coatings derived from: 100%

Eudragit® RL, 50% Eudragit® RL and 50% Eudragit® RS, and 10% Eudragit® RL: Eudragit® 90% RS. Of course, one skilled in the art will recognize that acrylic polymers such as Eudragit® L may also be used.

20

In other preferred embodiments, the hydrophobic polymers that can be used to coat the substrates of the present invention are a hydrophobic alkylcellulose material such as methylcellulose. Those skilled in the art will recognize that other cellulose polymers, for example other alkyl cellulose polymers, may partially replace some or all of the ethyl cellulose present in the hydrophobic polymer coatings of this invention.

One commercially available aqueous dispersion of ethylcellulose is Aquacoat (FMC Corp., Philadelphia, Pennsylvania, U.S.A.). Aquacoat® is prepared by dissolving ethylcellulose in a water-immiscible organic solvent and then emulsifying it in water in the presence of a surfactant and a stabilizer 17. After homogenization to submicron droplets, the organic solvent is evaporated in vacuo to form a pseudolatex. P last big int wave is not included in the pseudolatex during the manufacturing phase. Thus, before using this as a coating, it is necessary to thoroughly mix Aquacoat® with a suitable plasticizer before use.

Another aqueous dispersion of ethylcellulose is commercially available under the trademark Surelease (Colorcon, Inc., West Point Pennsylvania, U.S.A.). This product is prepared by incorporating a plasticizer into the dispersion 10 during the manufacturing process. The hot melt of the polymer, plasticizer (dibutyl sebacate) and stabilizer (oleic acid) is prepared as a homogeneous mixture which is then diluted with an alkaline solution to obtain an aqueous dispersion which can be applied directly to the substrates.

In those embodiments of the present invention where the coating comprises an aqueous dispersion of a hydrophobic polymer, the inclusion of an effective amount of plasticizer in the aqueous dispersion of the hydrophobic polymer improves the physical properties of the film. For example, since cytyl cellulose has a relatively high glass transition temperature and does not form flexible films under normal coating conditions, it is necessary to plasticize ethyl cellulose before using it as a coating material. Generally, the amount of plasticizer included in the coating solution is based on the concentration of the film former, e.g., in most cases from about 1 to about 50 weight percent of the film former. However, the concentration of the plasticizer can only be properly determined through careful testing in a given k.o. coating solution and application method.

Examples of suitable plasticizers for ethyl cellulose are water-insoluble plasticizers such as dibutyl sebacate, diethyl phthalate, triethyl citrate, tributyl citrate and triacetin, although other water-insoluble plasticizers, such as monoacetyls, diisoglycerides, etc., may be used. Triethyl citrate is particularly preferred.

Examples of suitable plasticizers for the acrylic polymers of this invention are citric acid esters such as triethyl citrate NF XVI, tributyl citrate, dibutyl phthalate and optionally 1,2-propylene glycol, polyethylene glycols, propylene glycol, diethyl phthalate, , 10 phthalate esters, castor oil, etc.). Triethyl citrate is particularly preferred.

The slow release profile of the formulations of the invention may be varied, for example, by varying the thickness of the hydrophobic coating, changing the particular hydrophobic material used, or changing the relative amounts of various acrylic resin lacquers, changing the amount polymer, by adding more ingredients or fillers, changing the manufacturing process, etc.

20

Slow release spheroids or beads coated with an opioid may be prepared, e.g., by dissolving the opioid analgesic in water and then spraying the solution on a substrate, for example nu pariel 18/20 beads, using a Wurster insert. Optionally, additional additive ingredients may also be added before the beads are coated to better bind the opioid to substrates and / or to color the solution, etc. For example, a product containing hydroxypropylmethylcellulose, with or without dye, may be added to the solution and mixed. 1 hour) before applying to beads. The resulting coated substrate, in this example beads, may then optionally be coated with a barrier agent to separate the therapeutically active agent from the hydrophobic sustained release coating. One example of a suitable barrier agent is one comprising hydroxypropylmethylcellulose. However, any film former known in the art may be used. It is preferred that the limiting agent does not affect the dissolution rate of the final product.

5

The opioid, HPMC protected (optional) beads can then be coated with a hydrophobic polymer, preferably in an effective amount of plasticizer.

The coating solutions of the present invention preferably contain, in addition to the film formed, a plasticizer and a solvent system (i.e., water) to provide elegance to the dye and to separate the product. Color may be added to the solution of the therapeutically active agent in place of or in addition to the hydrophobic aqueous polymer dispersion.

A plasticized aqueous dispersion of a hydrophobic polymer may be applied to a substrate comprising a therapeutically active agent by injection using any suitable injection equipment known in the art. The preferred method employs a Wurster fluidized bedding system in which an air jet, which is injected underneath, fluidizes the shell material and provides drying while the acrylic polymer coating is sprayed on. Sufficient aqueous dispersion of the hydrophobic polymer to provide a predetermined slow release of said therapeutically active agent when exposed to aqueous solutions, e.g. Opadry®, optionally added to the beads. This coating, if any, is applied to substantially reduce bead agglomeration.

Next, the coated beads are cured to obtain a stabilized release rate of the therapeutically active agent.

20

When the coating comprises an aqueous dispersion of ethylcellulose, the coated substrate is preferably cured at a temperature higher than the glass transition temperature of the coating solution (i.e., ethylcellulose) and at a relative humidity of about 60% to about 100% until a final cure of 60 ° C. about 60% to about 100% for about 48 to about 72 hours, as described in U.S. Patent No. 5,273,760, which is incorporated herein by reference.

In preferred embodiments of the present invention directed to acrylic coating, the stabilized product is obtained by curing the coated substrate in an oven at a temperature above the Tg of the plasticized acrylic polymer for a period of time whereby optimum temperature values and a given formulation time are determined experimentally. In certain embodiments of the present invention, the stabilized product is obtained by curing in an oven at about 45 ° C for about 24 hours or longer, as described in U.S. Patent No. 5,286,493, which is incorporated herein by reference.

The release of the therapeutically active agent from the sustained release formulation of the present invention can still be influenced, i.e.. adjust to a specific rate by adding one or more release modifying agents, or by sequencing one or more passageways through the coating. The ratio of hydrophobic polymer to water-soluble material is determined e.g. required release rate and solubilization properties of selected materials.

Release-modifying agents that act as pore-formers may be organic and / or inorganic and include materials that can be dissolved, leached, or leached from the coating in the environment of use. The pore formers may comprise one or more hydrophilic polymers, such as hydroxypropyl methylcellulose. The sustained release coatings of this invention may also contain wear enhancing agents such as starch and gums. The sustained release coatings of this invention may also include materials useful for making microporous laminates in an environment of use, such as polycarbonates consisting of linear polyesters of carbonic acids having carbonate groups in the polymer chain. The release modifying agent may also comprise a semipermeable polymer. In many preferred embodiments, the release modifying agent is selected from hydroxypropylmethylcellulose, lactose, metal stearates, and mixtures thereof. The sustained release coatings of this invention may also include exit means comprising at least one passageway, orifice, or the like. The passageway may be formed by methods such as those disclosed in U.S. Patent Nos. 3,845,770; 3,916,889; 4,063,064; and 4,088,864 (all of which are incorporated herein by reference). The passage can have any shape, such as circular, triangular, square, elliptical, irregular, etc.

In other embodiments of the present invention, a multiparticulate slow release matrix can be used. Suitable materials for incorporation into the sustained release matrix include (a) Hydrophilic polymers such as gums, cellulose salts, acrylic resins, and protein derived materials. Of these polymers, cellulose ethers, especially hydroxyalkyl celluloses and carboxyalkyl celluloses, are preferred. The oral dosage form may contain from 1 to 80% (w / w) of at least one hydrophilic or hydrophobic polymer.

(b) Highly digestible, long chain (CgC50, especially C12-C40), substituted or unsubstituted hydrocarbons such as fatty acids, fatty alcohols, glyceryl esters of fatty acids, mineral and vegetable oils and waxes. Hydrocarbons having a melting point of 25-90 ° C are preferred. Of these, long chain hydrocarbon materials, fatty (aliphatic) alcohols are preferred. The oral dosage form may contain up to 60% (w / w) of at least one easily digestible long chain hydrocarbon.

22 (c) Polyalkylene glycols. The oral dosage form may contain up to 60% (w / w) of at least one polyalkylene glycol.

For example, a suitable matrix may be one comprising at least one water-soluble hydroxyalkyl cellulose, at least one C12-C36, preferably C14-C20, aliphatic alcohol, and optionally at least one polyalkylene glycol. Said at least one hydroxyalkylcellulose is preferably hydroxy (C 1 -C 4) alkylcellulose, such as hydroxypropylcellulose, hydroxypropylmethylcellulose and especially hydroxyethylcellulose. The amount of said at least one hydroxyalkyl cellulose in this oral dosage form is determined, inter aha, by the exact rate of opioid release required. Said at least one aliphatic alcohol may be, for example, lauryl alcohol, myristyl alcohol or stearyl alcohol. In certain preferred embodiments, the at least one aliphatic alcohol is cetyl alcohol or cetostearyl alcohol. The amount of said at least one aliphatic alcohol in this oral dosage form will be determined as per the exact rate of opioid release required above. It also depends on whether or not at least one polyalkyl glycol is present in the oral dosage form. When this at least one polyalkylene glycol is not present, the 20 oral dosage forms preferably contain from 20% to 50% (w / w) of at least one aliphatic alcohol. When the at least one polyalkylene glycol is present in the oral dosage form, the weight of the at least one aliphatic alcohol and at least one polyalkylene glycol together preferably represents from about 20% to about 50% (w / w) of the total 25 doses.

In one embodiment, for example, the ratio of at least one hydroxyalkyl cellulose or acrylic resin to at least one aliphatic alcohol / polyalkylene glycol determines, to a certain extent, the rate of opioid release from formulation. A ratio of 1: 2 to 1: 4 of at least one hydroxyalkylcellulose and at least one of 23 aliphatic alcohols / poly (alkylene glycol) is preferred, with a ratio of 1: 3 to 1: 4 being particularly preferred.

The at least one polyalkylene glycol may be, for example, polypropylene glycol or preferably polyethylene glycol. Preferably, the at least one polyalkylene glycol has a numerical average molecular weight of 1,000 to 15,000, especially 1,500 to 12,000.

Another suitable slow-release matrix could comprise alkylcellulose, especially ethylcellulose, a C12-C36 aliphatic alcohol and optionally polyalkylene glycol.

In addition to the above ingredients, the sustained release matrix may also contain suitable amounts of other substances, such as diluents, lubricants, binders, granulating aids, colorants, perfumes, and lubricants conventional in the pharmaceutical art.

These sustained release matrices may be prepared, for example, by 20 (a) forming granules comprising at least one water-soluble hydroxyalkyl cellulose and an opioid or an opioid salt, (b) mixing the hydroxyalkyl cellulose containing the granules with at least one C12-C36 aliphatic alcohol; and shaping the granules. Preferably, the granules are formed by wet granulating hydroxyalkylcellulose / opioid with water. For example, the amount of water added during the wet granulation step may be 1.5 to 5 times, especially 1.75 to 3.5 times, the dry weight of Opioid.

30 24

In still other alternative embodiments, the spheronizing agent, together with the active ingredient, can be spheronized to form spheroids. Microcrystalline cellulose is preferred, although very small aqueous granules of lactose are preferably used in slow release formulations of morphine sulfate prepared by powder coating techniques. A suitable microcrystalline cellulose is, for example, a material sold by Avicel PH 101 (trademark, FMC Corporation). In such embodiments, in addition to the active ingredient and the spheronizing agent, the spheroids may also contain a binder. Suitable binders, such as low viscosity water soluble polymers, are well known to those skilled in the pharmaceutical art. However, water soluble hydroxy lower alkyl cellulose such as hydroxypropyl cellulose is preferred. In addition (or alternatively) the spheroids may contain a water insoluble polymer, especially an acrylic polymer, an acrylic copolymer such as methacrylic acid ethyl acrylate copolymer or ethyl cellulose. In such embodiments, the sustained release coating generally comprises a water-insoluble material, such as (a) a wax, alone or in admixture with a fatty alcohol; or (b) scllac or zinc.

The substrates of this invention may also be prepared by melt pelletization techniques. Under such conditions, the opioid in finely divided form is combined with the binder (also in particulate form) and other optional seaway ingredients, and then the mixture is pelletized, e.g. The pellets (granules, spheres) can then be screened to obtain pellets of desired size. The binder is preferably in particulate form and has a melting point above about 40 ° C. Suitable binders include, for example, hydrogenated castor oil, hydrogenated vegetable oil, other hydrogenated fats, fatty alcohols, fatty acid esters, fatty acid glycerides and the like.

In certain preferred embodiments of the present invention, an effective amount of the opioid in immediate release form is included in a 24 hour slow release dosage unit opioid formulation. The immediate release form of the opioid is included in an amount that effectively shortens the time to obtain the maximum concentration of opioid in the blood (e.g., plasma). In such embodiments, an effective amount of the opioid in immediate release form can be coated with the substrates of this invention. For example, when the opioid extended release formulation is dependent on the controlled release coating, the immediate release layer may be coated with a controlled release coating. On the other hand, the immediate release layer can be coated on the surface of the substrates when the opioid is incorporated in an adjustable release matrix. When a plurality of sustained release substrates comprising an effective opioid dosage unit (e.g., multiparticulate pellets, pellets, spheres, beads, and the like) are incorporated into a hard gelatin capsule, the immediate release opioid dose portion may be incorporated into the gelatin capsule by incorporating an opioid . Alternatively, the gelatin capsule itself may be coated with an opioid immediate release layer. One of ordinary skill in the art would know of other alternative ways of incorporating an immediate release 20 opioid moiety into a dosage unit. Such options are included in the appended claims. It has been found that including such an effective amount of immediate release opioid in a dosage unit significantly reduces the relatively intense pain experience in patients.

The dosage form can be obtained by preparing the dosage form according to the methods described above or by other means known to those skilled in the pharmaceutical art.

In addition to the above, sustained release opioid formulations may also be formulated as tablets. The tablet may then contain, in addition to an opioid and a retarder, suitable amounts of other substances, e.g. diluents, lubricants, binders, 26 granulating agents, colorants, flavors and lubricants, which are conventional in the pharmaceutical art up to about 50% by weight of the particles. Specific examples of pharmaceutically acceptable carriers and excipients that can be used to formulate oral dosage forms are described in Handbook of Pharmaceutical Excipients, the American Pharmaceutical Association (1986), the disclosure of which is incorporated herein by reference. Techniques and compositions for making solid oral dosage forms are described in Pharmaceutical Dosage Forms: Tablets (Lieberman, Lachman & Schwartz, Editors) Second Edition, published by Marcel 10 Dekker, Inc., the disclosure of which is incorporated herein by reference. Techniques and compositions for making tablets (compressed and formed), capsules (hard and soft gelatin) and pills are also described in Remington's Phannaceutieal Sciences. (Arthur Osol, author), 1553-1593 (1980), the contents of which are incorporated herein by reference.

15

To titrate a human patient with inventive slow-release opioid formulations, multiple blood samples are taken from patients at intervals of time. The samples thus obtained are then tested to determine the plasma level of the opioid analgesic and possible active metabolites (metabolites). The values thus obtained can then be used to determine additional pharmacokinetic parameters. It is determined whether the patient has received an appropriate pharmacodynamic response for said dosage form. This assay is, for example, a reference to predefined blood values, a comparison comparing the results of subjective pain tests performed on a patient, the adverse drug profile of the drug in the patient, or the like. The assay may then lead to upward or downward adjustment of the dose as needed.

The slow release dosage unit dosage form will continue to be administered in dosage unit dosage form in order to maintain an appropriate pharmacodynamic response. Preferably, a suitable pharmacodynamic response lasts about 12 to about 24 hours, most preferably about 24 hours or more.

27

Dosage delivery of the slow release dosage form is continued during the dosage unit dosage form to maintain a suitable pharmacodynamic response with said slow release dosage form.

5

If necessary, the above steps are repeated until the determination of a suitable pharmacodynamic response is achieved in a sustained release dosage unit form.

According to the above method, the patient may be titrated with a slow release 10 opioid analgesic dosage form. Subsequent maintenance therapy can be obtained with the same sustained release dosage form.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

The following examples illustrate various aspects of the present invention. They are not made to limit the requirements in any way.

EXAMPLES 1-2 20

In Example 1, morphine sulfate sustained release beads were prepared with a 5% w / w sustained release coating comprising Eudragit® RS, which included a 10% immediate release morphilyl sulfate coating. Example 2 prepared slow release morphine sulfate beads with an 8% w / w 25 slow release coating comprising Eudragit® RS, which included a 10% immediate release morphine sulfate coating.

Morphine sulfate beads were first made using a rotor processing technique. The formula of the morphine sulfate beads to which the sustained release coating was applied is shown in the following Table 1: TABLE 1 28 5 Amt / unit

Ingredient (mg) Percent (%)

Morphine Sulfate Powder 30 mg 14.3%

Lactose very small granules 42.5 mg 20.2% PVP 2.5 mg 1.2% 10 Sugar beads 18/20 125 mg 59.4%

Purified water qs mg -

Onadrv Red YS-1-1841 10.5 mg 4.9%

A total of 210.5 mg 100.0% The slow release coating was then applied to the morphline sulfate beads. The sustained release coating formula of Examples 1 and 2 is shown in Table 2 below:

Example 1 Example 2

Ingredients)% (mg)% 5 Morphine based beads 89.45 mg86.7189.5 mg83.0%

Retardant coating

Eudragit® RS 30 D 9.5 mg 4.3% 15.2 mg 6.7% Titrated Citrate Talc 10 Purified Water Top Coat

Morphine Sulphate Powder 3.0 mg 1.4% 3.0 mg 1.3%

Opadry Red YS-1-1841 10.8 mg 5.0% 11.4 mg 5.0%

Purified water qs - qs - 15 Total 218.45 mg 100.0% 228.2 mg / 100.0%

The slow release coating was prepared as follows. Eudragit® RS 30D was plasticized with trityl citrate and talc for about 30 minutes. The addition of morphine sulfate beads was placed in a Glatkin Wurster Inserk equipped with a 1.2 mm syringe nozzle and the beads were coated for 5% and 8% weight gain in Examples 1 and 8, respectively. 2. The final protective Opadry dispersion was then applied as a topcoat to the Wurster insert. When this oh finished, the beads were cured for two days in a dry oven at 45 ° C. The cured beads were then filled into gelatin capsules at a strength of 30 mg.

25

Solubility testing was performed on gelatin capsules in U.S.P. Via Apparatus II (Paddle Method). The capsules were placed in 700 ml of simulated gastric fluid (without enzymes) for the first hour at 100 rpm at 37 ° C and then placed in 900 incubated simulated gastric fluid (without enzymes) after the first 30 hours. The percentage of morphsulphate dissolved over time in Examples 1 and 2 is shown in the following Table 3:

Percentage of dissolved morphilic sulphate 5 TimeExample 1 Example 2 1 hour 11.9% 10.2% 2 hours 15.4% 11.3% 4 hours 28.1% 12.8% 8 hours 58.3% 16.4% 10 12 hours 79.2% 29.6% 18 hours 92.0% 58.1% 24 hours 96.6% 73.2%

Clinical evaluation of Examples 1-2

Ten normal healthy mice were enrolled in a four-way, randomized, single dose, general pharmacokinetic / pharmacodynamic study to evaluate the effect of food on the pharmacokinetic / pharmacodynamic profile of Example 1 compared to the same product 20 and CR 30 mg morphine tablet (MS Contin), fasting pharmacodynamic parameters. A comparison of Example 2 with a morphine-releasable 30 mg tablet (MS Contin®) was also made. Plasma morphine concentrations were used to calculate pharmacokinetic parameters that include: (a) absorption and elimination rates; (b) the area under the 25 curve (AUC); (c) maximum plasma concentration (Cmax); (d) time to maximum plasma concentration (Tmax); (e) Ty2 (elimination). The pharmacodynamic effect relative to the plasma concentrations of morphine was described by data obtained with the following pharmacodynamic parameters: mood, calm, respiratory rate, pupillometer and protocol.

30 31

Clinical evaluations in the laboratory

Blood samples were collected for hematology (hemoglobin, hematocrit, red blood cell count, white blood cell count by differentiation, platelet count) and for blood chemistry analysis (calcium, inorganic phosphate, uric acid, total protein, albumin, cholate, oxaloacetic transaminase (SGOT), Serum glutamic pyruvate transaminase (SGPT), fasting blood glucose, blood urea nitrogen (BUN), serum creatinine) before and after study (72 hours) (i.e., 72 hours after phase 4 dose). A urine sample was collected for urine analysis (specific gravity, glucose, albumin, bile, pH, acetone, microscopic examination) before and after the study (72 hours) (i.e., 72 hours after the phase 4 dose). Urine analysis of mice for anti-illicit drugs was performed during the screening procedure and immediately prior to each dose of the 15 drugs under study (first day of phases 1-4).

Plasma morphine concentrations were determined from blood samples taken just prior to dosing (0 hours) and after 0.5, 1.2, 2.5, 3, 3.5, 20, 4, 5, 6, 8, 10, 12 , 18, 24, 36, 48 and 72 hours after each dose.

Blood samples, each of approximately 10 ml, were taken into tubes containing a solution of ethylenediaminetetraacetic acid (EDTA) as an anticoagulant. After centrifugation, the plasma was pipetted into two 5 ml labeled polypropylene tubes and cooled to -20 ° C. One aliquot of 25 samples was taken to a designated analytical laboratory in sufficient quantity of carbonated ice to keep them frozen for 2 days, and another aliquot was kept frozen at the study site.

Pharmacodynamic measurements

The following pharmacodynamic parameters were measured immediately prior to baseline blood sampling (30 minutes prior to dosing) and after 0.5, 1, 2, 2.5 3, 3.5, 4, 5, 6, 8, 10, 12 , 18, 24, 36, 48 and 72 hours after each dose.

5

Mental state (measured by visual analogue scale (VAS) on target protocol plate) 10 minutes prior to blood sampling. The VAS was attached to one end as the worst state of mind and the other as the best state of mind.

10 Calm (measured with VAS on target protocol plate) - 10 minutes before blood sample. The VAS was attached to one end as a sleeping space and to the other as a waking space.

Breathing rate (breaths per minute) - 5 minutes after taking a blood sample. 15 (Information was recorded on the subject's record disk.)

Pupillary size - measured by pupillometry - 5 minutes after blood sampling. Only the left eye was measured at all times. (The information was recorded on the subject's record disk.) 20

Figure 1 is a graph of mean sedation versus time curve in Example 1 (fasted). Figure 2 is a graph of mean quiescent versus time curve in Example 2 (fasted). Figure 3 is a graph of average breathing rate versus time curve in Example 1 (fasted). Figure 4 is a graph of average respiratory rate versus time curve in Example 2 (fasted).

Plasma morphine concentrations were determined by high performance liquid chromatography. Arithmetic mean Cmax, Tmax, AUC, half-lives were calculated from individual plasma morphine concentrations over time and the oral bioavailability data were as shown in Tables 4 and 5: 33 TABLE 4 10

Pharmacokinetic MS Contin®Esim. 2Esini. 1 parameter ('Fasted')

C max * (ng / ml) 13.05 3.95 * 5.42 * 5.87 * 20

Tmax (hours) 2.45 15.05 * 5.85 6.90 AUC (0.72) 25 (hr-ng / ml) 101.11 136.10 * 109.37 111.33 AUC (0.00) (hr-ng / ml) 101.31 155.44 * 117.77 114.45 30 34 T./2(elim;hrs) 2.81 89.68 * 19.02 10.34 T./2 (abs ; hrs) 1.20 3.96 2.51 3.48 5 TABLE 5 35 (A = MS Contin; B = Example 2 fasted; C = Example 1 eaten; and D = Example 1 fasted) 5

Pharmaco-Fo (%) F0 (%) F0 (%) F0 (%) Kinetic90% C.I.90% C.I.90% C.I.90% C.I. parametersB vs. AYC vs. AYD vs. AYD vs. Cl 10 Cma * 32.24 39.88 42.50 106.57 (ng / ml) {15.7- (23.3- (26.0- (65 , 2- 48.7) 56.5) 59.0) 148.0)

Tmax 608.27 232.33 290.48 125.03 15 (hours) (435.6- (58.8- (117.9- (50.7- 780.9) 405.8) 463.11) 199 , 3) AUC 134.53 105.02 106.04 100.97 (0.72) {111.1- (81.5- (82.6- (78.6-20 (hr-ng / ml))) 158 , (0) 128.6) 129.5) 123.3) AUC 151.04 112.91 108.09 95.73 (0.00) {112.6- (81.8- (77.1- (68) , 3- (hr-ng / ml) 189.4) 144.0) 139.0) 123.1) 25 T./23076.7 689.41 374.01 54.25 (elim; hrs) (2256, 7- (24.9 - (- 286.8 - (- 41.6 - 3896.7) 1353.9) 1034.9) 150.1) 30 T./2 281.21 167.18 239.86 143.48 (abs; hrs) (- 123.1 - (- 11.7 - (62.4- (37.2-36 685.5) 346.0) 417.3) 249.8)

Statistically significant (p <0.0500) compared to MC Contin® (based on non-transfer data)

Fo (%) = Oral Bioavailability (Least Mean Squared Test / Mean Least Squared Mean).

Table 6 gives mean (± S.D.) plasma amorine concentrations (ng / ml) 10 after dosing with MS Contin® and Examples 1 and 2.

TABLE 6

Mean (± S.D.) Plasma Morphine Concentrations (ng / ml) after 15 Doses with MS Contin® and Morphine

AikaMS Contin®Esim. 2Esim. lEsim. 1 ('hourly ~) 20 mg (fasted-fasted-fasted-fasted) ~ 0.000.00 ± 0.000.00 ± 0.000.00 ± 0.000.00 ± 0.00 0.503.04 ± 2.072.22 ± 1.091.83 ± 1,350.51 ± 0.79 1,006.78 ± 4,191.89 db 0.542.09 ± 1.071.46 ± 0.95 2.0011.4 db 5.701.60 db 0.692.33 ± 0.982,46 ± 0.91 2.5010.30 ± 6.461 , 78 ± 1,162.22 ± 0.882.51 ± 0.88 25 3,009.40 ± 5,411,54 db 0,972,61 ± 1,123,47 ± 1,77 3,508,09 db 4,481,34 db 0,982,82 ± 1,393,03 ± 1,26 4,007,11 db 3,781,06 db 0,493,60 ± 2,503,41 ± 1,82 5,007,25 db 4,711,54 db 1,214,09 ± 2,243,80 ± 1,29 6,005,27 db 3,311,20 db 0,774 , 11 ± 1,744,23 ± 1,68 30 8,003,19 db 1,991,58 db 1,003,80 ± 1,464,46 ± 1,51 10,01,87 ± 1,002,62 ± 1,053,57 ± 1,444,16 ± 1, 37 37 12,01,70 ± 0,763,10 ± 1,642,83 ± 0,644,33 ± 2,20 18,01,23 ± 0,673,04 ± 1,112,40 ± 1,131,85 ± 1,12 24,01,38 ± 0.962,54 ± 0,551,82 ± 1,011,71 ± 0,73 36.00. 85 ± 0.642.58 ± 1.041.35 ± 0.701.19 ± 0.40 5 48.00.22 ± 0.471.48 ± 0.480.69 ± 1.080.73 ± 0.56 72.00. 05 ± 0.160.54 ± 0.660.16 ± 0.330.22 ± 0.46

Table 7 gives mean (± S.D.) pharmacokinetic parameters after dosing with MS Contin® and Examples 1-2.

10 DISEASE 7 7

Mean (± S.D.) Pharmacokinetic Parameters after MS Contin Dosage Formulation of each morphineTielme 5 MS Contin® 30 mgEsim. 2Esim. lEsim. 1

Parameliacal ¥ fasting crumbs ni fasting rivets ¥ sweat) 10 Cmax 13.05 3.95 5.42 5.87 (ng / ml) ± 5.22 ± 1.55 ± 2.26 ± 2.07

Tmax 2.45 15.05 5.85 6.90 (hrs) ± 0.86 ± 9.51 ± 1.92 ± 3.18 15 AUC10U1136,10109.37 ± 111.33 (0.72) ± 41, 91 ± 34.5 8 ± 43.06 ± 3 6.2 (hr-ng / ml) 3 1 20

When comparing Example 1 (fasting) with MS Contin® (fasting), there was a statistically significant difference in CIIiax. There were no significant differences between the two treatments for Tmax, AUC (0.72), AUC (0.00) and Ty2 (elim.) Or Ty2 (abs.). 90% confidence intervals for all pharmacokinetic parameters were 80-120% out of range.

When comparing Example 1 (fed) with MS Contin (fasting), there was a statistically significant difference between the Cmax values. There were no statistically significant differences between the two treatments for Tmax, AUC (0.72), AUC (0.00) and 39 Τι / 2 (body) or Τ · / 2 (abs). 90% confidence intervals for all pharmacokinetic parameters were 80-120% out of range.

Comparison of Example 1 with the fed and fasted state showed no significant differences in Cmax, TmaA, AUC (0.72), AUC (0.00) and Ty2 (organ) or Ty2 (abs). The 90% confidence intervals for all pharmacokinetic parameters were 80-120% out of range.

The role of food in the absorption of Example 1 is characterized by higher Cmax and higher Tmax and TV, (abs) values. However, the extent of absorption (based on AUC) differs by less than 3% in the fed and fasted state.

When comparing Example 2 (fasting) with MS Contin® (fasting), there were statistically significant differences in Cmax, Tmax, AUC (0.72), AUC (0.00) and Ty2 (elim). There was no statistically significant difference between the two treatments for Ty2 (abs). The 90% confidence intervals for all pharmacokinetic parameters were outside the 80-120% range.

20

Based on a 90% confidence interval analysis, the beads of Example 1 in fasted or fed condition did not match the MS Contin® tablets, nor did the beads of Example 2. Although the experimental controlled release morphine formulations were not bioequivalent to MS Contin® tablets, both had relatively lower Cmax and higher Tmax and apparent Ty 2 (elim) values.

Linear regression of each pharmacodynamic parameter at log-transformed concentrations for each subject and treatment 30 resulted in 48 regressions (out of 240) (48/240; 20%) with a R2 value of 20% or higher, of which 8 (8/240; 3 %) was a value that was 50% or higher. When 40 were analyzed by treatment alone, all R values were less than 10%. These values do not indicate any significant linear relationship between the pharmacodynamic measurements and log concentrations.

Examination of mean hysteresis curves showed a possible relationship between pupil size and morphine concentration. In the case of MS Contin® and Example 1, pupil size tended to decrease as morphine concentration increased and increase as morphine concentration decreased. Figure 5 is a graph of mean pupil size versus time curve in Example 1 (fasting). Figure 6-10 is a graph showing the average pupil size over time in Example 2 (fasting). No relationship was observed between morphine concentrations and other parameters.

Two subjects (20%) reported six unpleasant experiences with MS 15 Contin®. Three subjects (30%) had six uncomfortable experiences with controlled release morphine beads (Example 1; fasting). One subject in each of the following treatment groups experienced one unpleasant experience: Example 1 (feed) and Example 2 (fasting). No clinically significant changes in physical examinations or ECG results, clinical laboratory values, or vital measurements occurred during the study.

Inquiry about the effect of modified special medicine

The query was a 22-item query modification used by Jasinski, D.R. (1977) 25 Assessment of the Abuse Potential of Morphine-Like Drugs (Methods Used in Man). In Drug Addiction I (Martin, W.R., ed.) Pp. 197-258. Springer-Verlag, New York; and Preston, K.L., Jasinski, D.R., and Testa, M. (1991) Abuse Potential and Pharmacological Comparison of Tramadol and Morphine. Drug and Alcohol Dependence 27: 7-17. The questionnaire consisted of 10 items that the subject and 30 researchers had to answer. The sections related to the brands of opiate agonist drugs and were as follows: 41

Target Questions 1. Do you know any drug effects? 5 2. Does the skin tighten? 3. Are you relaxed? 4. Are you sleepy? 5. Are you drunk? 6. Are you nervous? 10 7.Are you full of energy? 8. Do you feel the need to talk? 9. Are you feeling sick? 10. Are you confused? 15 The subject evaluates these issues by placing a vertical mark in the 100 mm VAS. with a "none" sign at one end and "terribly" at the other.

Investigates im questions 20 1. Does the drug have any effects on the subject? 2. Does the target scratch itself? 3. Is the destination relaxed? 4. Is the subject drunk? 5. Is the subject nervous? 25 6.Does the item speak? 7. Does the item vomit? 8. Is the item confusing? 9. Is the destination restless? 10. Does the subject sweat? 30 42

The researcher evaluates each of these questions by placing a vertical mark on a 100 mm VAS with the word "none" at one end and the word "extremely" at the other. Figure 7 is a graphical representation of the subject's questions versus time curve in Example 1 (fasting). Figure 8 is a graphical representation of the questions of item 5 against the average time curve in Example 2 (fasting).

Unpleasant experiences

The unpleasant experiences, whether spontaneously reported or directly evaluated by 10 questions, were immediately recorded and evaluated by the principal investigator to determine the severity, duration and beginning of the corrective measurements. The subjects were followed until they returned to baseline.

43

analyzes

Plasma morphine assays were performed using high performance liquid chromatography (HPLC). The limit of determination was 0.5 ng / mL. Annex V contains 5 analytical reports of plasmamorphine.

Statistical and pharmacometric methods

Parameters 10

Serum plasma morphine values collected from each subject and treatment were corrected for the zero hour value by subtracting the zero hour value from all subsequent values in that Saija.

15 No series of data in which the zero hour value exceeded the minimum analytical sensitivity, as noted above, were excluded from the data analysis. The following parameters were evaluated for each subject and treatment using baseline-corrected plasma levels: 20 Cmax (ng / ml) maximum observed plasma morphine value

Tmax (hours) The time of occurrence of Cmax relative to the time of dose

Ty2 (body; hours) - apparent plasma elimination half-life of plasamorphine calculated as 25 in the following formula: T 2/2 (body) 0.693 / Ke where Ke is the terminal first order apparent elimination rate constant calculated by PROC NLIN in SAS Release 6.07 ( SAS Institute, Cary, NC).

30 T / 2 (abs; hours) - apparent absorption half-life, calculated using the formula: 44 T./2 (abs) - 0.693 / Ka.

Figure 9 is a graph of the mean plasma morphine concentration time profile obtained by Comparative Example (MS Contin 30 mg) (Fasting) 5 compared to the capsules of Example 1 (during feeding and during fasting) and Example 2 (fasting).

From the above results, it can be seen that the formulation of Example 1 yields a higher and earlier Cmax but slightly lower morphine absorption than the formulation of Example 2. Visual examination of time effect data for quiescence, respiratory rate, pupil size, and composite values of the opioid effect questionnaire, which subjects responded at different times after each treatment, provide a greater magnitude of each pharmacodynamic endpoint in earlier portions of time effect curves (e.g., 4-8 hours).

EXAMPLE 3

Beads with more morphine sulfate were produced using 20 powder coating techniques in the Glatt Rotor Processor. The formulation of the high-content beads is shown in the following Table 8: TABLE 8 25 High Load Percentage Ingredient bead fmg / unitY%)

Morphine sulfate powder 30.0 mg63.3%

Lactose 6.0 mg / 2.7% 30 Povidone C-30 1.25 mg 2.6%

Sugar beads 7.75 mg 16.4% 45

Opadry 2.37 mg 5.0%

Purified water qs -

Total 47.37 mg / 100.0% 5 The slow release coating comprised an acrylic polymer (i.e., Eudragit® RL). HPMC protective coating was also included between the Eudragit layer and the morphine immediate release layer for improved stability. The formula for the slow release coating of Example 1 is shown in the following Table 9:

Anit / UnitPro Ent Ingredients (mg) (%) 15 Morphine (High Volume) Beads42.63 mg78.8%

Slow release coating Eudragit RS 30D 2.1 mg 3.9%

Eudragit RL 30D 0.05 mg 0.1%

Triethyl citrate 0.45 mg 0.8% 20 Talc 0.85 mg 1.6% Topcoats

Opadry Blue YS-1-10542A 2.45 mg 4.5%

Purified water qs -

Morphine Sulfate Powder 3.0 mg 5.5% Opadry Blue YS-1-10542A 2.5 5 mg 4.8%

Purified water qs -

Total 54.08 mg 100.0%

Slow release and immediate release coatings were applied as follows. Eudragit RL 30D was plasticized with triethyl citrate and talc for about 30 minutes. A load of morphine sulfate beads was added to Glatk Wurster 46

To an inserter equipped with a 1.2 mm syringe mouthpiece and the beads were coated for 5% weight gain. The final protective Opadry dispersion topcoat was applied in a Wurster Insert. When finished, the beads were cured for two days in a dry oven at 45 ° C. The cured beads were then filled into gelatin capsules at a strength of 30 mg. The cured beads were then filled into gelatin capsules at a strength of 30 mg.

The capsules were then subjected to dissolution tests. Dissolution tests on the final products were performed via the USP Device II (Paddle Method). The capsules were placed in 700 mL of 10 simulated gastric fluid (without enzymes) for the first hour at 100 rpm and 37 ° C, and then placed in 900 mL of simulated gastric fluid (without enzymes) after the first hour. The results of solubility testing are shown in the following Table 10: 15 TABLE 10

Percentage Time Morphine Sulfate Dissolved 1 Hour 1.7% 2 hours 12.1% 20 4 hours 22.0% 8 hours 45.3% 12 hours 63.7% 18 hours 81.8% 24 hours 92.5% 25

Clinical evaluation of Example 3

Thirteen normal healthy mice were included in a five-way randomized study to analyze the effect of food on the pharmacokinetic and pharmacodynamic properties of a single dose of 30 mg of Example 3 (as capsules). The pharmacokinetic and pharmacodynamic results of the 47 sustained release formulations in these fed and fasted subjects were also compared with those obtained in the MS Contin 30 mg fed and fasted subjects. Plasma morphine levels were used to calculate pharmacokinetic parameters which included: (a) apparent absorption and elimination rates; (b) area under the curve (AUC); (c) maximum plasma concentration (Cmax); (d) time to reach maximum plasma concentration (Tmax); (e) Ty 2 (abs), and (f) Ty 2 (elim). Pharmacodynamic effects were analyzed and evaluated based on state of mind, sedation, respiratory rate, pupal Ilo metry, and 10 questionnaires on subject behavior.

Plasma morphine concentrations were determined by a high performance liquid chromatography method. All subjects completed the study and were included in bio-pharmaceutical analyzes. The arithmetic mean Cmax, Tmax, AUC, 15 mean half-lives were calculated from the individual plasma morphine concentrations over time, and the oral bioavailability data are shown in the following Tables 11 and 12: 20 TABLE 11 25

FarmakokineettinenEsim. 3Esim. 3MS Contin® Parameter_f Eaten YOUR Fasting Tonnuf) 30

C max (ng / ml) 5.45 4.03 11.65 48 T max (hours) 8.04 12.92 2.77 AUC (0.72) (hr-ng / ml) 1 18.12140.79114, 05 AUC (0.00) (hr-ng / ml) 137.67166.19114.05 T./2 (elim; hrs) 21.19 54.51 1.26 5 T, / 2 (abs; hrs) 3 , 12 2.44 3.34 49 TABLE 12

Pharmaco-Fo (%) Ex. 3 vs.

5 kinetic90% C.I.MS Contin® parameter fEsim. 3: svonvtvs. fasted)! both in fasted state)

Cmax 164.36 29.54 (ng / ml) (113.1-21.5.6) (14.3- 44.7) 10 T, λ max 53.49514.28 (hours) (13.3-93, 7) (306.8-721.7) AUC (0.72) 89.93119.35 15 (hr-ng / ml) (64.8-115.1) (89.2-149.5) AUC ( 0.00) 86.56143.48 (hr-ng / ml) (62.5 - 110.6) (108.6-178.1) 20 T./2 (elim; hrs) 34.531609.0 ( 7.4-61.7) (1170-2048) T./2 (abs; hrs) 135.27191.45 (83.5-187.0) (92.0-290.9) 25

Fo (%) = Oral Bioavailability (Test Mean / Reference Mean) 30 50

Table 13 gives mean (± S.D.) plasma amorphine concentrations (ng / ml) after dosing with MS Contin® and Example 3.

51 TABLE 13

Mean plasma morphine concentrations ± standard deviation after dosing 5 TimeEsim. 3Esim. 3MS Contin® ftuntia) 30 mg Eat30 mg Fasted30 mg Eat 0.000.00 ± 0.000.00 ± 0.000.00 ± 0.00 0.500,201 ± 0.4472.00 ± 1.483.42 ± 1.82 1.000. 331 ± 0.4792.27 db 0.7996.09 ± 2.03 10 2.001.65 ± 1.532.19 ± 0.9368.82 ± 2.61 2.503.06 ± 1.042.20 ± 0.7989.12 ± 2 , 97 3,003,53 ± 1,822,24 ± 1,059,91 ± 5,32 3,503,06 ± 1,162,87 ± 1,948,83 ± 3,58 4,003,23 db 1,042,33 ± 1,138,12 ± 3,26 15 5,004, 01 ± 1,502.91 ± 0.9337.79 db 3.47 6.004.00 ± 2,092.96 db 1,246.07 ± 3.69 8,004.03 ± 1,902.58 ± 1,244.68 ± 3.88 10.03,95 ± 1,891.95 ± 0.9652.61 db 1.43 12.03.20 db 1.472.18 ± 0.9831.58 ± 0.815 20 18.02.06 ± 1.022.75 ± 1.531.46 ± 0.745 24.02 , 10 ± 0.9632.72 db 0.9711.34 ± 0.890 36.01.16 ± 1.052.65 db 1.181.08 db 0.971 48.0 0.872 ± 0.6811.53 ± 0.8510.528 db 0.831 72.00. 300 ± 0.5290,468 ± 0.6500.00 ± 0.00 25

Table 14 gives mean (± S.D.) pharmacokinetic parameters after dosing with MS Contin® and Example 3.

52 TABLE 14

Mean pharmacokinetic parameters ± standard deviation after administration of each formulation 5

Example 3First. 3MS Contin®

Parameter30 mg svönvt30 mg fasted30 mg fasted 10 Cmax (ng / ml) 5.45 ± 1.684.03 ± 1.5511.65 ± 4.82 Tmax (hrs) 8.04 ± 8.3112.92 ± 14.662.77 ± 0.927 15 AUC (0.72) (hr-ng / ml) 118.12 ± 36.77140.79 ± 51.23114.05 ± 42.42

Ratios of AUC for the least squares means for the 30 mg capsules in the fed and fasted conditions of Example 3 indicate that the AUCs in the fed conditions are ± 20% of the values obtained in the fasted state. Cmax was 64% higher in the fed state. The T max value in the fed state was about 50% of that obtained in the fasted state. The apparent absorption rate was about 35% higher in the fed state and the apparent elimination rate in the fed state was about 35% of the fasted state, indicating that the presence of food slows the absorption of morphine and the elimination rate increases.

53

Least squares mean AUC ratios for the 30 mg capsules of Example 3 and the MS Contin® 30 mg tablet indicate that the AUC (0.72) values in Example 3 are ± 20% of the MS Contin® values and the AUC (0.00) values are 44% higher in Example 5 of Example 3. The Cmax of Example 3 was 29.5% of the value of MS Contin®. The value of Tmax in the fed state was five times that of Example 3. The apparent absorption rate was approximately 91% higher in the case of Example 3 and the apparent elimination of Example 3 was 16 times that of MS Contin, indicating that the absorption and elimination of morphine is slower in Example 3.

10

Linear regression of each pharmacodynamic parameter at log-transformed concentrations at each target and treatment resulted in 74 of the 315 regressions (24%) having a R2 of 20% or higher and 12 of the 315 (4%) having a value of 15, which was 50% or higher. When analyzed by treatment alone, there were no R2 values greater than 10%. Of the individual R2 values greater than 20%, 21 appeared in 63 regressions (33%) on the subject's modified specific drug response questionnaire at log concentration, and 7 of the 63 (11%) 20 had greater than 50%. These values indicate a possible linear relationship between the log concentrations and the MSDEQ values of the subjects. Examination of mean hysteresis curves also indicates a possible association between morphine concentration and target MSDEQ status. In each formulation, the subject's modified specific drug effect score score tended to increase as morphine concentration increased and decrease as morphine concentration decreased. No association was observed between morphine concentrations and other pharmacodynamic parameters.

Figure 10 is a graph of the mean plasma morphine concentration-30 thio-time profile obtained from Comparative Example (MS Contin 30 mg) (fasted state) versus the capsules of Example 3 (fed and fasted).

54

Figure 11 is a graphical representation of the mean quiescent versus time curve in Example 3 (fasted). Figure 12 is a graph of average respiratory rate versus time in Example 3 (fasting). Figure 13 is a graphical representation of the average pupil size over time in Example 3 (fasting). FIG.

55 EXAMPLE 4

Beads with higher loading of morphine sulfate were produced using powder coating technology in a Glatt Rotor Processor. The formulation of the high 5 load beads is shown in the following Table 15.

TABLE 15

High Load Percentage 10 Ingredient bead mg / unit (%)

Morphine Sulphate Powder60.0 mg56.4%

Lactose 12.0 mg / l, 3%

Eudragit RS30D 4.16 mg 3.9%

Povidone C-30 8.31 mg 7.8% 15 S ocher beads 16.80 mg 15.8%

Opadry 5.06 mg 4.8%

Purified water qs ---

Yields 0.36 mg 100% These immediate release base beads were made using powder coating technology in a Glatt Rotor Processor.

The slow release coating comprised an ethyl cellulose acrylic polymer (i.e., 25 Aquacoat ECD 30). The HPMC protective coating was also incorporated after the Aquacoat layer to further improve stability. The formula for the slow release coating of Example 1 is shown in Table 16 below.

56 TABLE 16

IngredientAmt / unit (mg) Percentage f% 5 Morphine-based beads (high load) 106.33 mg73.1%

Retardant coating 10

Aquacoat ECD 30 23.13 mg / 5.9%

Methocel E5 Premium 3.46mg 2.4% 15 Triethyl Citrate 5.32mg 3.6 Purified Water qs --- 20 Final Layer

Opadry Blue YS-1-10542A 7.28 mg 5.0%

Purified water qs --- 25

A total of 54.08 mg 100.0% 30 The final release coating slow release coating was applied as follows: The combination of Aquacoat ECD 30 and Methocel E5 Premium was plasticized with 57 triethyl citrate for approximately 30 minutes. A load of morphine sulfate beads was added to a Glatt Wurster Inserk equipped with a 1.2 mm syringe nozzle and the beads were coated for 25% weight gain. Once the retarder was complete, the beads were cured for three days in a temperature / humidity chamber at 60 ° C / 80% RH. The cured beads were then dried in a hot day oven at 60 ° C. The cured dry beads were added to a Glatt Wurster Inserk equipped with a 1.2 mm syringe nozzle and the final protective Opadry dispersion topcoat was then applied. The finished sustained release beads, together with low-content, immediate-release morphine sulfate beads, were individually filled with 10 mg of the same gelatin capsules at a strength of 60 mg. Slow release beads comprised 90% or 54 mg of strength and immediate release beads comprised 10% or 6 mg of capsule strength.

The capsules were then subjected to a dissolution test. The leaching test was performed on the finished 15 products by the USP Apparatus II (Paddle Method). The capsules were placed in 700 inhaled simulated gastric fluid (without enzymes) for the first hour at 100 rpm and 37 ° C, and then placed in 900 ml of simulated intestinal fluid (without enzymes) after the first hour. The results of solubility testing are shown in Table 17 below.

20 TABLE 17

Time% dissolved morphine sulfate 1 hour 10.4% 25 2 hours 11.4% 4 hours 17.5% 8 hours 31.8% 12 hours 54.0% 18 hours 88.6% 30 24 hours 102.3% 58 EXAMPLE 58 5

Beads with higher levels of morphine sulfate were produced using powder coating technology in a Glatt Rotor processor. The formulation of high 5 morphine sulfate beads is shown in Table 18 in Example 5.

The slow release coating comprised an acrylic polymer (i.e., Eudragit RS / RL). HPMC protective coating was also incorporated after the Eudragit layer to further improve stability. The formula for the slow release coating of Example 5 is shown in the following Table 18.

TABLE 18 15 IngredientAmt / unit (mg) Percentage (%)

Morphine based beads (high content) 106.33 mg87.96% 20

Retardant coating

Eudragit RS 30 D 5.05 mg 4.18% 25 Eudragit RL 30 D 0.27 mg 0.22%

Triethyl citrate 1.06 mg 0.88%

Talc 2.13 mg 1.76% 30 59

Final top coat

Opadry Blue YS-1-10542A 6.04 mg 5.0% 5 Purified Water qs ---

Total 120.88 mg / 100.0% 10

The slow release and final coatings were applied as follows. Eudragit RS / RL 30D was plasticized with triethyl citrate and talc for about 30 minutes. The amount of morphine sulfate beads was loaded into a Glattai Wurster Insert equipped with a 1.2 mm syringe nozzle and the beads were coated with 5% weight gain. The final protective Opadry dispersion topcoat was then applied in a Wurster Insert. When finished, the beads were cured for two days in a dry oven at 45 ° C. The cured beads were then filled into gelatin capsules at a strength of 60 mg.

The capsules were subjected to dissolution tests. Solubility tests were performed on final products USP Apparatus II (Paddle Method). The capsules were placed in 700 incubated simulated gastric fluid (without enzyme) for the first hour at 100 rpm and 37 ° C, and then placed in 900 incubated simulated intestinal fluid (without enzymes) after the first nucleus. The results of the leaching tests are shown in the following 25, Table 19.

TABLE 19

Time% dissolved morphine sulfate 1 hour 10.4% 30 2 hours 11.4% 4 hours 17.5% 60 8 hours 31.8% 12 hours 54.0% 18 hours 88.6% 24 hours 102.3% 5 EXAMPLE 6

Matriisihelmet

Matrix beads with higher levels of morphine sulfate were produced using 10 powder bed techniques on a Glatt Rotor processor. The formulation of the high load matrix beads is shown in Table 20 below.

TABLE 20 15 High Load Percentage Ingredient bead mg / unit (%)

Morphine Sulphate Powder 60.0 mg 46.0%

Lactose 12.0 mg 9.2%

Eudragit RS 30D 29.10 mg 22.4% 20 Povidone C-30 5.80 mg 4.5%

Sugar Beads 16.80 mg 12.9%

Opadry 6.50 mg 5.0%

Purified water gs ----

Total 130.20 mg 100% 25

The matrix component consists of an ethylcellulose polymer (i.e., Aquacoat ECD 30). HPMC barrier coating was also included after the watercoating layer to further improve stability.

30 Matrix beads were made as follows. Aquacoat ECD 30 was plasticized with tributyl citrate for about 30 minutes. Morphine sulfate powder and lactose 61 were mixed for about 5 minutes in a Hobart mixer. The amount of sugar beads was added to a Glatt rotor inlet equipped with a 1.2mm syringe nozzle / powder feed assembly. A suitable powder feeder was located above the syringe nozzle / powder feed assembly and loaded with 5 morphine sulfate / lactose blends. The morphine sulfate / lactose mixture is then deposited on the sugar beads using a plasticized hydrophobic polymer dispersion (i.e., Aquacoat ECD 30 and tributyl citrate) as a binder. When the deposition process 011 was completed, the final protective Opadry dispersion topcoat was applied. The beads were cured for one day in a dry oven at 60 ° C. The cured beads 10 were then filled into gelatin capsules at a strength of 60 mg.

The capsules were then subjected to dissolution testing. Solvent testing was performed on the final product by the USP Apparatus II (Paddle Method). The capsules were placed in 700 ml of simulated gastric fluid without enzymes for the first hour at 100 rpm and 37 ° C, and then placed in 900 volumes of simulated intestinal fluid (without enzyme) after the first hour. The results of the leaching test are shown in Table 21 below.

TABLE 21

Time% dissolved morphine sulfate 20 1 hour 32.4% 2 hours 44.8% 4 hours 59.6% 8 hours 76.6% 12 hours 88.0% 25 18 hours 97.6% 24 hours 102.2%

CLINICAL EVALUATION OF EXAMPLES 4. 5 AND 6

Fourteen normal healthy subjects were enrolled in a six-way, randomized, open-label study to evaluate the effect of food on the pharmacokinetics and pharmacodynamics of a single dose of Example 1, 2 or 3 62 with or without food. Plasma samples were analyzed for morphine levels and the following pharmacokinetic results were calculated and reported in Table 22 below.

TABLE

Pharmacokinetic parameter per 60 mg dose 10 Example AUCCmaxTmax number (ng / m 1 lin (ng / m 1) (hours) 1 fasting 120 6.1 5.5 1 fed 131 8.3 8.8 2 fasted 149 11 , 3 6.7 15 2 fed 159 11.5 6.4 3 fasted 154 14.3 1.8 3 fed 154 12.7 2.8 EXAMPLE 7 20

Hvdromorphone HCl 8 mg once daily capsules Drug Amount 25 Hydromorphone Beads were prepared by dissolving hydromorphone HCl in water, adding Opadry / -5-1442 and stirring for about 1 hour to give a 20% w / v suspension. This suspension was then injected into the beads of a Nu-Pareil 18/20 sieve using a Wurster insert.

First coating 63

The loaded hydromorphone beads were then coated with 5% w / w Opadry Light Pink using a Wurster insert. This coating was applied as a protective coating.

5 Retardant coating

After the first coating, the hydromorphone beads were coated with a 5% weight loss coating of Eudragit RS 30D and Eudragit RL 30D in a 90:10 ratio, RS / RL. Addition of triethyl citrate 10 (plasticizer) and talc (anti-adherent) was also included in the Eudragit suspension. The Wurster insert was used to apply the coating suspension.

N atural pavement 15

After the retardation coating was complete, the final Opadry Light Pink topcoat was applied to the hydromorphone beads up to 5% weight gain using a Wurster insert. This coating was also applied as a protective coating.

20 Hardening

After the final coating was complete, the hydromorphone beads were cured at 45 ° C for 2 days.

25 Encapsulation

The beads were hand-filled into # 2 clear gelatin capsules at a strength of 8 mg hydromorphone HCl.

The formulation of Example 7 is shown in the following Table 23: 64 TABLE 23

Hydromorphone Hello 8 mg once daily capsules

Ingredient mg / capsule Quantity

Hydromorphone HCL 8.00

Opadry Light Pink (Y-5-1442) 4.00

Purified water1 q.s.

18/20 Sieve Sugar Balls 148.00 Coating

Opadry Light Pink (/ -5-1442) 8.40

Purified water1 q.s.

Retardant coating

Eudragit RS 30D2 7.60

Eudragit RL 30D2 0.80

Triethyl citrate 1.68

Talc 3.36

Purified water1 q.s.

Second coating

Opadry Light Pink (Y-5-1442) 9.60

Purified water1 q.s.

Encapsulation

Size # 2 clear hard gelatin capsules n / a

Total fill weight 191.44 mg 65 - - Used in processing and residual moisture only.

2 Dry weight 66

dissolution tests

The above capsules were tested using the USP methodology and the following results were obtained:

Time Original 1 hour 17.2 2 hours 48.4 4 hours 77.4 8 hours 93.3 12 hours 97.2 18 hours 98.8 24 hours 98.8

A single-dose randomized general bioavailability study was conducted with the above 8 mg controlled-release hydromorphone HCl capsules and two immediate-release 4 mg tablets (Dilaudid) as a control in 10 fed and fasted conditions. Blood samples were analyzed for hydromorphone levels and the following pharmacokinetic parameters were calculated. The results are shown in the following Table 24: 67 TABLE 24

Group AUC% IR Tmax Cmax T /, (pg / ml / hr) (hr) (pg / ml) (abs) CR fasted * 21059 101 4.9 1259 2.56 CR eaten * 25833 106 4.6 1721 3, 92 IR Fasted * "20903 100 0.85 3816 0.18 IR Eaten ** 24460 100 1.15 3766 0.32 * CR = Example 7 ** IR = Dilaudid 5 The examples given herein are not intended to be exclusive. Many of the present invention variations would be apparent to those skilled in the art and are considered to be within the scope of the appended claims.

Claims (12)

A method of producing a sustained-release opioid formulation given orally once a day, comprising several substrates containing a dose of an opioid analogue and an effective amount of at least one retardant material, characterized in that the process comprises steps , wherein: A) several delayed release substrates are produced by coating several inert beads with a portion of said opioid analogue dose and by coating said coated inert beads with said retarding material, and B) said delayed release substrate with immediate release of the residual said opioid analgesic dose in a proportion which achieves release of said opioid analgesic from the well-received formulation at an effective rate for producing an analgesic effect after oral administration to a human patient for at least about 24 hours and initially a rapid increase. the plasma concentration of said opioid so that an absorption half-life of 1 to about 8 hours is achieved upon administration to a patient in a fasted state. A method according to claim 1, characterized in that said opioid is tramadol or a site thereof. 3. A process according to claim 1 or 2, characterized in that said retarding material is selected from a group consisting of an acrylic polymer, an alkyl cellulose, shellac, zein, hydrogenated vegetable oil, hydrogenated castor oil and mixtures of some of the above. Method according to any of claims 13, characterized in that said delayed release formulation given orally provides an absorption half-life of about 1-6 hours. 30 Process according to any of claims 1-3, characterized in that said delayed release formulation given orally provides an absorption half-life of about 1-3 hours. 5 Method according to any of claims 1-5, characterized in that a peak plasma level of said opioid in vivo is achieved about 10 hours after administration. Process according to any of claims 1-6, characterized in that said delayed release formulation comprises several substrates, said opioid including each of said substrates having a diameter of 0.1 - 3 mm. Method according to any of claims 1-7, characterized in that the instant release opioid analgesic coating is coated onto the delayed release substrates. Method according to any one of claims 1-8, characterized in that said substrate is enclosed in a capsule. 20 Method according to any of claims 1-9, characterized in that said substrate is manufactured in a form selected from spheroids, beads, microspheres, grains, pellets, ion exchange resin beads, grains and mixtures thereof. Method according to any of claims 18, characterized in that said delayed release formulation is manufactured as a tablet. Method according to any of the claims 17, characterized in that the instant release mold is enclosed in the form of powder or grits in a capsule with the delayed release substrates.